Aedes aegypti mosquitoes transmit Dengue and Yellow Fever virus, and Culex quinquefasciatus mosquitoes transmit the West Nile virus and filarial parasite Wuchereria bancrofti to hundreds of millions of people. Methods for inhibiting vector- human contact, particularly in conjunction with other existing programs of vector control, may play a critical role in controlling the spread of these diseases. Female mosquitoes, like most other blood-feeding insects, identify their human hosts primarily using olfactory cues like carbon dioxide in exhaled breath, as well as other odors present in skin emanations. The goal of this research is to modify odor-guided host-seeking behavior of Aedes and Culex mosquitoes using cheap and environmentally safe odor molecules that can be used in very small quantities as effective trapping agents, masking agents and repellents. To achieve these goals we will focus on functional analyses of the CO2 sensing neuron. CO2 is detected in this neuron using a receptor comprising three members of the Gustatory receptor family that encode a highly conserved heteromeric CO2 receptor. We plan to use an integrated platform of neurophysiology, chemical- informatics, molecular, genetic and behavioral methods to; 1) identify effective volatile agonists and antagonists for the CO2 receptors, 2) test the effects of these molecules on behavior of female Aedes and Culex mosquitoes, in particular, for the ability of antagonists in masking agents or repellents, and 3) agonists to improve trapping efficiency. In preliminary studies, we have identified a few volatile inhibitors and activators of the CO2 receptor in Aedes and Culex. We now propose to conduct further studies to identify more effective chemicals that inhibit or activate physiological and behavioral responses to CO2 in female mosquitoes. Successful completion of the proposed studies will lead to the development of a new generation of effective and safe insect repellents and lures that act by modifying CO2 receptor function.